tbuckley/cabot-search huggingface dataset:
Anatomic distribution of local recurrence of nasopharyngeal carcinoma in the Era of IMRT: Suggestion of modification of clinical target volume delineation.
Authors: Xiaomin Ou, Jiazhou Wang, Wenbin Yan, Xueguan Lu, Hongmei Ying, Xiayun He, Chaosu Hu
Journal: Journal of Clinical Oncology (2022)

e18060 Background: Target volume delineation in nasopharyngeal carcinoma (NPC) remains a challenge because of the narrow therapeutic margin. There are no-well established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony structure and experience from conventional two and three- dimensional radiation. The aim of our study, is to clarify different anatomic distribution of local recurrence of NPC based on various T stages and spread patterns, provide a high-risk map of local recurrence of NPC, and thus provide suggestion for modification of CTV delineation based on T stages and spread patterns. Methods: We retrospectively enrolled 869 patients with newly diagnosed nonmetastatic NPC treated with definitive IMRT in our institution. With a median follow-up of 54.4 months, 72 patients developed local failure. All the cases of local failure were reviewed and those of local residual disease were excluded. After that, 52 cases with tracaeble primary radiotherapy plans and MR imaging of local recurrence were included in this study. Gross tumor volume of local recurrence (GTVr) and normal structures were delineated in each recurrent patient on primary CT of radiotherapy. The overlap of normal structures with GTVr were analyzed, as well as the stepwise patterns of tumor spread in NPC, based on different T stages and relapsed risk (≥5%, ≥10%, ≥20%, etc). Results: The anatomic distributions of local recurrence of various primary T stages were compared between early and late stages of NPC. Of note, these structures were significantly highly involved in T3/4 cases, compared with T1/2 cases, including lateral pterygoid muscle, inferior orbital fissure，posterior ethmoid sinus，cavernous sinus as well as hypoglossal canal. As for tumor spread patterns of local relapse, most cases relapsed in the nasopharynx and retropharyngeal lymph node (38.5%), followed by anterior-lateral tumor extension (via nasal cavity-pterygoid process-pterygopalatine fossa, 17.31%), posterior tumor extension (via prevertebral muscle-clivus, 13.46%), anterior-superior extension (via nasal cavity-ethmoid sinus-sphenoidal sinus,13.46%), superior extension(via foramen lacerum-cavernous sinus, 11.54%), etc. Finally, we depicted a map of high-risk area based on different T stages and relapsed risk (≥5%, ≥10%, ≥20%). Conclusions: Comprehensive analysis of local recurrence distributions and tumor spread patterns in real-world IMRT provides important reference for modification of CTV delineation for primary NPC. Certain structures such as cavernous sinus and lateral pterygoid muscle are not routinely recommended in the delineation of high-risk CTV for T1-2 disease. Future individualized delineations should be based on relapsed risk and tumor spread patterns.
Proteogenomic detection of circulating biomarkers for clinical oncology.
Authors: Qimin Quan, Joshua Ritchey, Joe Wilkinson, Alaina Kaiser, John Geanacopoulos, John Boyce
Journal: Journal of Clinical Oncology (2022)

e15010 Background: Circulating biomarkers have the potential to detect cancer in its earliest stages and monitor patients in remission. The integration of proteogenomics in circulating biomarkers may transform the molecular diagnostics of cancer and accelerate basic and clinical oncology research. Proteomics bridges the gaps of functional information lost due to post-transcriptional and post-translational modifications in a genomic approach. A recent study showed that adding just 8 protein biomarkers to a panel of circulating DNA biomarkers increased the diagnostic accuracy up to 98% sensitivity and 99% specificity. However, the proteogenomic approach normally requires the use of multiple different assay technologies and laboratory workflows, including mass spectrometry. Methods: MosaicNeedles are densely integrated nanoneedle sensors fabricated on a planar substrate that integrates proteogenomic analysis in one platform. 94,000 sensors with more than 2 billion total nanoneedles can be integrated on to a standard SBS plate, which can be configured into 96, 384 or 1536 well format. Each sensor contains an array of nanoneedles, dedicated to detecting one analyte of interest. All nanoneedles comprising the same sensor are functionalized with the same capture probes. The capture probe can be either an antibody for protein detection or an oligonucleotide with a specific target sequence to a DNA fragment, mRNA, or miRNA of interest. Results: At low analyte concentration, the binding of proteins to the nanoneedles follows a Poisson distribution. Therefore, statistically, no more than one molecule is bound per nanoneedle. A further addition of aptamers or antibodies will form a sandwich complex with the target analyte. Since each of the nanoneedles has an intrinsic optical resonance spectrum and will red-shift as the sandwich complex forms on its surface, the number of analytes can be quantitated by simply counting the number of nanoneedles that display a color change. At high analyte concentration, each nanoneedle has more than one analyte, so the number of analytes can be calculated by averaging the spectrum shifts of all nanoneedles. This combined single molecule counting (digital) and spectrum shift (analog) analysis allows the platform to detect both high abundance and low abundance protein analytes in one reaction. A 10,000-plex study can be achieved with a total of 2.5 billion nanoneedles on a 50mm by 50mm consumable. In this consumable, a 2,000-plex proteome and 8,000 cell-free DNA fragments can be detected. Conclusions: A full proteogenomic quantification can be performed on the NanoMosaic platform in one reaction with high sensitivity and large dynamic range. It simplifies the workflow and allows users to integrate proteomic and genomic information to discover new circulating biomarkers.
Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma.
Authors: David Stephen Shulman, Priscilla Merriam, Edwin Choy, Lillian M. Guenther, Kerri Cavanaugh, Pei-Chi Kao, Andrew Posner, Grace Fairchild, Emma Barker, Kimberly Stegmaier, Brian D. Crompton, Wendy B. London, Steven G. DuBois
Journal: Journal of Clinical Oncology (2022)

e23507 Background: Ewing sarcoma (EwS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. CDK4 is a known genomic vulnerability in EwS, but an unappealing monotherapy target given propensity for innate resistance. In laboratory studies to identify targets synergistic with CDK4 inhibition, IGF-1R scored highly. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF-1R monoclonal antibody) for patients with relapsed or refractory EwS. Methods: This was a prospective open-label, non-randomized, single-center, phase 2 study (NCT04129151) for patients with relapsed EwS and RECIST measurable disease. Patients with relapsed EwS ≥12 years and a documented fusion consistent with EwS were eligible. Patients initially received Palbociclib 125 mg on days 1-21 and ganitumab 18 mg/kg on days 1 and 15 of a 28-day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A one-stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. Results: Ten evaluable patients enrolled between 5/2019-8/2021. The study closed 12/2021 due to lack of ganitumab drug supply. The median age at enrollment was 25.7 years (range 12.3-40.1; Table). The median duration of therapy was 2.5 months (range = 0.9-10.8). There were no complete or partial responders. Three of 10 patients had stable disease for &gt; 4 cycles and 2 had stable disease at completion of planned therapy or study closure. 6-month PFS was 30±14.5%. Two patients had cycle 1 hematologic DLTs triggering the pre-defined toxicity rule; the palbociclib dose was subsequently reduced to 100 mg daily for 21 days. Among the remaining 8 patients, two had cycle 1 hematologic DLTs at the 100 mg dose. 80% of patients had grade 3/4 AEs; the most commons AEs were neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Total IGF-1 testing demonstrated intrapatient elevations in serum levels after a single cycle of therapy. Analysis of serial ctDNA samples is ongoing. Conclusions: Four responders out of 15 were required to reject the null hypothesis of a 10% response rate. With 0/10 responders, we concluded that this combination lacked adequate therapeutic activity for further study. The combination was tolerable at a palbociclib dose of 100 mg, with primarily hematologic toxicity in patients with relapsed EwS. Clinical trial information: NCT04129151. [Table: see text]
Cohort study of patients with oligorecurrent prostate cancer: Oncological outcomes of patients treated with salvage lymph node dissection via PSMA radioguided surgery.
Authors: Sophie Knipper, Mehrdad Mehdi Irai, Ricarda Simon, Daniel Koehler, Isabel Rauscher, Matthias Eiber, Fijs WB van Leeuwen, Pim van Leeuwen, Hilda de Barros, Henk G. van der Poel, Lars Budaeus, Thomas Steuber, Markus Graefen, Pierre Tennstedt, Matthias Heck, Thomas Horn, Tobias Maurer
Journal: Journal of Clinical Oncology (2022)

5009 Background: Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) allows detection of small and/or atypically localized metastatic prostate cancer (PCa) lesions. In a subset of patients with recurrent oligometastatic PCa salvage surgery with PSMA-targeted radioguidance (PSMA-RGS) may be of value. We aimed to evaluate the oncological outcomes of salvage PSMA-RGS for oligo-recurrent PCa and determine predictive preoperative factors of improved outcomes. Methods: In this cohort study within two tertiary care centers, patients with biochemical recurrence (BCR) after radical prostatectomy (RP) and imaging with PSMA PET receiving salvage PSMA-RGS between 2014 and 2020 were analyzed. Kaplan-Meier and multivariable Cox regression models adjusted for various parameters were used to test for BCR-free survival (BFS) and therapy-free survival (TFS) differences. Postoperative complications were classified according to Clavien-Dindo. Results: Overall, 364 patients were assessed. At PSMA-RGS, median (IQR) age and preoperative PSA was 67 (61-71) years and 1.0 (0.5-1.9) ng/ml. Metastatic soft-tissue lesions from PCa metastases could be removed in 343 (94.2%) patients. Within three months from surgery, 24 (6.6%) patients suffered from Clavien-Dindo complications grade III-IV. During follow-up, 225 patients experienced BCR and 121 patients received further therapy. Median follow-up for patients who did not experience BCR and who did not receive further therapy was 10.8 months and 10.3 months, respectively. Median (IQR) BFS and TFS was 7.8 (5.4-10.5) and 35.5 months (25.9-45.9 months). At two years of follow-up, BFS rate was 31.9% and TFS rate was 58.0%. In multivariable analyses, higher preoperative PSA (HR: 1.1), higher number of PSMA-avid lesions on preoperative imaging (HR: 1.2) and multiple (pelvic plus retroperitoneal) localizations (HR: 1.9), as well as retroperitoneal localization (HR: 2.0) of lesions in PSMA PET imaging were independent predictors of BCR after PSMA-RGS. Limitations are the retrospective design and lack of a control group. Conclusions: As salvage surgery in oligo-recurrent PCa currently constitutes an experimental treatment approach careful patient selection is mandatory based on life expectancy, low PSA values and low number of PSMA PET avid lesions located in the pelvis. Further studies are needed to confirm our findings and define the oncological value of salvage surgical procedures in oligo-recurrent PCa.
Predictive and prognostic value of carcinoembryonic antigen (CEA) on maintenance therapy with 5-fluoruracil/leucovorin plus panitumumab or 5-fluoruracil/leucovorin alone in RAS wildtype metastatic colorectal cancer: Evaluation of the phase II PanaMa trial (AIO KRK 0212).
Authors: Annika Kurreck, Meinolf Karthaus, Stefan Fruehauf, Ullrich Graeven, Lothar Mueller, Alexander Koenig, Ludwig von Weikersthal, Eray Goekkurt, Siegfried Haas, Arndt Stahler, Volker Heinemann, Swantje Held, Annabel Helga Sophie Alig, Beeke Hoppe, Andreas Jay Kind, Stefan Kasper, Sebastian Stintzing, Tanja Trarbach, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2022)

3587 Background: Carcinoembryonic antigen (CEA) may reflect response to antitumor treatment in metastatic colorectal cancer (mCRC). The predictive value of CEA has not yet been proven for subsequent maintenance therapy. This analysis aims to evaluate the predictive and prognostic value of pre- and post-induction treatment CEA on maintenance with 5-fluoruracil/leucovorin (FU/FA) plus panitumumab (pmab) [arm A] or FU/FA alone [arm B] in RAS wildtype mCRC patients treated within the PanaMa trial. Methods: Patients with CEA measurements (pre- and post-induction therapy) were grouped as normal (both measurements ≤5 ug/l), stable (between +25% and -25%), decreasing (&lt;-25%), and increasing (&gt;+25%) CEA. Survival parameters (overall survival (OS), progression-free survival (PFS) from initiation of maintenance therapy) were expressed by the Kaplan-Meier method and compared by log-rank testing, and Cox regression. The objective response (OR) to maintenance therapy was analyzed by chi-square testing. Results: Out of 248 patients in the in the full analysis set, 245 patients were eligible for CEA analysis. Normal CEA occurred in 58 (23.7%), stable CEA in 16 (6.5%), decreasing CEA in 161 (65.7%), and increasing CEA in 10 (4.1%) patients. In the subgroup of decreasing CEA, there was a significant difference in the prediction of OR between both treatment arms with a better positive predictive value for the pmab-containing maintenance (44.0% vs. 27.5%, p=0.032). Increasing compared to decreasing CEA was associated with unfavourable survival outcome of maintenance irrespective of treatment arm (Table). Conclusions: CEA kinetics during induction therapy appears to have a predictive value for subsequent maintenance, notably pmab-based. Besides that, CEA levels had a significant impact on survival parameters of maintenance irrespective of the addition of pmab to FU/FA. This analysis is limited by the small number of patients in the subgroup of increasing CEA. Clinical trial information: NCT01991873. [Table: see text]
Predicting major bleeding events in anticoagulated cancer patients with venous thromboembolism using real-world data and machine learning.
Authors: Andrés J. Muñoz Martín, María Luisa Palacios, Juan Carlos Souto, Berta Obispo, Jorge Aparicio, Andres Garcia-Palomo, Antonio Sanchez, Cristina Aguayo, David Gutierrez Abad, Maria Carmen Viñuela-Benéitez, Diego Benavent, Miren Taberna, Daniel Arumi, Miguel Ángel Hernández-Presa
Journal: Journal of Clinical Oncology (2022)

e18744 Background: Evidence regarding the clinical predictors of bleeding risk in patients with cancer and venous thromboembolism (VTE) is lacking. Our aim was to develop a predictive model to assess the risk of major bleeding (MB) in anticoagulant-treated patients with active cancer during the first 6 months following VTE diagnosis. Methods: Observational, retrospective, and multicenter study based on the secondary analysis of unstructured clinical data in electronic health records (EHRs). Using the EHRead technology, based on Natural Language Processing (NLP) and machine learning (ML), data were collected from EHRs from 9 Spanish hospitals between 2014 and 2018. The study population comprised all adult cancer patients with a diagnosis of VTE under anticoagulant treatment and no history of MB. This population was downsampled to prevent bias and class imbalance. A total of 94 patient characteristics were explored, and Random Forest (RF) feature selection was performed to identify the most relevant predictors. Multiple algorithms were used to train different prediction models, which were subsequently validated in a hold-out dataset. The model with the best performance metrics (i.e., ROC-AUC) was selected as the final model. Results: Among a source population of 2,893,208 patients, 21,227 anticoagulant-treated patients with VTE and active cancer were identified from EHRs. Of these, 53.9% men, with a median age (Q1, Q3) of 70 (59,80) years. The median duration of follow up across all patients was 0.7 (0.11, 2.03) years. During the study period, estimated in-hospital prevalence of cancer-related VTE was 5.8 %. The most common type of VTE at baseline was deep vein thrombosis (68.2 % of patients), followed by pulmonary embolism (28.4%). The most frequent primary cancers were colorectal (10.1%) and lung cancer (8.5 %). Of all trained and validated models, the RF approach yielded the best performance, with a ROC-AUC = 0.7. The following predictors of MB were identified: hemoglobin levels, presence of metastasis, patient’s age, platelet count, leukocyte count, and serum creatinine levels. Conclusions: This is the first multicenter study to use NLP to extract the unstructured information from EHRs to develop a predictive model for MB in anticoagulated cancer patients with VTE. These results may improve the prevention and management of bleeding in these patients.
Landscape of homologous recombination reversion mutations in pancreaticobiliary malignancies.
Authors: Brennan James Decker, Susan M. Domchek, Kate Nathanson, Shannon Bailey, Natalie Danziger, James Thornton, Mark Hartman, Chenming Cui, Lei Yang, Smruthy Sivakumar, Russell Madison, Ethan Sokol, Alexa Betzig Schrock, Bahar Yilmazel, Douglas A Mata, Christine Vietz, Jeffrey S. Ross, Julia Andrea Elvin, Geoffrey R. Oxnard, Kim Anna Reiss
Journal: Journal of Clinical Oncology (2022)

4156 Background: Homologous recombination (HR) pathway reversion mutations (REV) are emerging treatment resistance biomarkers for platinum and PARP inhibitor therapy. The wide diversity of REV presents a diagnostic challenge. We implemented an automated computational approach to detect REV and examined the genomic features of REV-positive pancreaticobiliary cancers. Methods: Retrospective study of tissue (n = 31,124) and liquid biopsy (n = 3,870) samples from patients undergoing hybrid-capture comprehensive genomic profiling during routine clinical care 11/2012-03/2021. A proprietary algorithm tested samples for seven distinct REV mechanisms in BRCA1, BRCA2, or PALB2. For subjects with multiple samples, the earliest REV-positive sample was used for downstream analyses. Results: 5.3% (1,866/34,994) of biliary and pancreatic primary tumors harbored one or more pathogenic variants (PV) in BRCA1 (1.4%, n = 499), BRCA2 (3.2%, n = 1,119), or PALB2 (0.81%, n = 282). Among patients with at least one PV in these genes, 2.4% (45/1,866) had REV. The majority of REV involved BRCA2 (82%, 37/45), significantly higher than the proportion of BRCA2 PV in the cohort overall (59%, 1,119/1,900; p = 0.022). The remainder of REV involved either BRCA1 (8.9%, 4/45) or PALB2 (8.9%, 4/45). A total of 63 REV pairs were identified. The most frequent REV mechanism was an exonic non-frameshift deletion completely encompassing a PV (36%, 23/63), followed by a frameshift restoring the reading frame of a pathogenic frameshift (23%, 15/63), a benign missense replacing a PV at the same codon (17%, 11/63), and deletion with intronic breakpoints causing loss of a PV (17%, 11/63). REV were approximately equally prevalent in liquid biopsy (2.8%, 5/178) and tissue samples (2.4% 40/1,688; p = 0.72). A range of 1-9 REV were found per sample (liquid biopsy = 1-9, tissue = 1-2), and liquid biopsy samples had a higher median REV per sample compared to tissue (2.0 vs. 1.0; p &lt; 0.001), as well as a higher prevalence of multiple REV per sample (60% [3/5] vs 7.5% [3/40]; p = 0.013). These differences likely reflect stage of disease and sampling of multiple subclones. Conclusions: Although REV are uncommonly detected in pancreaticobiliary carcinomas, the presence of REV in BRCA2, BRCA1, and PALB2 in patients with pancreaticobiliary neoplasms supports HR as a therapeutic target in these cancers. Diverse REV mechanisms highlight a need for robust detection to incorporate REV in identifying treatment resistance and guiding therapy selection.
Genomic alteration in chromatin remodeling genes as a potential predictive biomarker for immunotherapy in gastric cancer.
Authors: Yongning Jia, Hongling Yuan, Yaqun Xin, Xiaofang Xing, Ziyu Li, Honglin Zhu
Journal: Journal of Clinical Oncology (2022)

e16083 Background: Gastric cancer (GC) is the fifth most incident and the fourth deadliest cancer worldwide, and currently immune checkpoint inhibitors have been approved for the treatment of patients with recurrent/metastatic GC. Studies have reported that the inactivation of chromatin remodeling complex may be a promising biomarker for immune checkpoint inhibitors (ICI) treatment. The aim of this study was to investigate the predictive value of chromatin remodeling genes on the response of ICIs in GC. Methods: We analyzed next-generation sequencing (NGS) data from three cohorts: the Chinese cohort (from GenetronHealth, n = 1013), the TCGA cohort (n = 434) and the ICI cohort (from the Memorial Sloan Kettering Cancer Center, n = 39). The abundance of tumor immune infiltrates was estimated by the tumor immune estimation resource (TIMER) 2.0 algorithm using gene expression data, and the Kaplan–Meier curves were used to determine survival differences. Results: In this study, we defined a set of chromatin remodeling genes containing PBRM1, ARID1A, ARID1B and ARID2. The loss-of-function mutations of these chromatin remodeling genes (CRG LOF ), including frameshift, nonsense and splice were identified in 176/1013 (17.4%) patients with GC in the Chinese cohort, which was significantly lower than those in the TCGA cohort (17.4% vs 27.6%, p = 0.00001). In both cohorts, patients with CRG LOF mutations exhibited higher tumor mutational burden (TMB) (all p &lt; 0.001) and PD-L1 expression (p &lt; 0.001 in the TCGA; p = 0.037 in the Chinese) than those without CRG LOF mutations. Next, we further analyzed the differences in tumor infiltrating lymphocytes (TILs) between CRG LOF and non-CRG LOF patients in the TCGA cohort, and the results showed that TILs level of CD8+ T cells (p &lt; 0.001), Dendritic cells (p = 0.0012) and Neutrophil cells (p &lt; 0.001) were all significantly higher in CRG LOF samples than non-CRG LOF ones. In addition, survival analysis found that CRG LOF mutation conferred no significant effect on patient outcome in the TCGA cohort, while in the ICI cohort, GC patients with CFG LOF mutations had significantly better prognosis after immunotherapy than patients with non-CRG LOF mutations(p = 0.042). Conclusions: Loss of chromatin remodeling subunits may impact response to immune checkpoint therapy and may predict patient outcomes in GC. Further study in larger cohorts of immunotherapy-treated patients and functional characterization of the CRG LOF mutations in the context of the tumor-immune microenvironment were needed.